OCRL1 Regulates the endocytic trafficking of APOER2 and reelin signaling

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dc.catalogadorgrr
dc.contributor.advisorMarzolo Canales, Maria Paz
dc.contributor.authorFuentealba Perez, Luz Maria
dc.contributor.otherPontificia Universidad Católica de Chile. Facultad de Ciencias Bológicas
dc.date.accessioned2024-08-26T15:21:08Z
dc.date.available2024-08-26T15:21:08Z
dc.date.issued2024
dc.date.updated2024-08-21T02:33:05Z
dc.descriptionTesis (Doctor in Biological Sciences, Cell and Molecular Biology mention)--Pontificia Unersidad Católica de Chile, 2024
dc.description.abstractLowe Syndrome is a severe disorder characterized by renal, ocular, and neurological signs. Mutations in the gene encoding the OCRL1 phosphatase are recognized as responsible for this syndrome. OCRL1 targets membrane phospholipids called phosphoinositides, with PI(4,5)P2 being the most common. The functions of OCRL1 are therefore associated with the regulation of intracellular trafficking and protein sorting. Mutations in OCRL1 affect different domains of the protein, both in enzymatic activity and in protein-binding domains, making it very difficult to describe a specific mechanism to explain this syndrome. Little is known about the nervous system, but neurological problems such as intellectual disability, behavioral disorders, and in some cases repetitive and stereotyped behaviors have been described. Interestingly, Reelin has functions in the development of the central nervous system, memory, and learning, and it signals by binding to membrane receptors of the LRP family, such as ApoER2/LRP8 and VLDLR, with ApoER2 being the most relevant. ApoER2 is internalized and recycled, and its intracellular trafficking is important for its function, as inhibiting its recycling significantly reduces Reelin signaling. Therefore, our study aims to elucidate whether the effects of OCRL1 on ApoER2 trafficking are reflected in a disturbance in Reelin signaling and, with this, to explain part of the neurological damage that occurs in Lowe Syndrome. Here, we show that ApoER2 passes through OCRL1-positive compartments and, furthermore, that the absence of OCRL1 disrupts the normal trafficking of ApoER2, affecting its availability at the cell surface and decreasing its half-life. Moreover, we detected a dysfunction in the signaling triggered by Reelin in our LS neuronal model. Thus, our study suggests that the disruption of the ApoER2/Reelin signaling pathway due to OCRL1 dysfunction may be a contributing factor to the neurological manifestations observed in Lowe Syndrome patients.
dc.fechaingreso.objetodigital2024-08-21
dc.format.extent148 páginas
dc.fuente.origenAutoarchivo
dc.identifier.doi10.7764/tesisUC/BIO/87672
dc.identifier.urihttps://doi.org/10.7764/tesisUC/BIO/87672
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/87672
dc.information.autorucFacultad de Ciencias Biológicas; Marzolo Canales, Maria Paz; 0000-0002-2328-2464; 72595
dc.information.autorucFacultad de Ciencias Biológicas; Fuentealba Perez, Luz Maria; 0000-0001-5472-5267; 1050265
dc.language.isoen
dc.nota.accesocontenido completo
dc.rightsacceso abierto
dc.rights.licenseAtribución-NoComercial-CompartirIgual 4.0 Internacional (CC BY-NC-SA 4.0)
dc.rights.urihttps://creativecommons.org/licenses/by-nc-sa/4.0/deed.es
dc.subject.ddc610
dc.subject.deweyMedicina y saludes_ES
dc.subject.ods03 Good health and well-being
dc.subject.odspa03 Salud y bienestar
dc.titleOCRL1 Regulates the endocytic trafficking of APOER2 and reelin signaling
dc.typetesis doctoral
sipa.codpersvinculados72595
sipa.codpersvinculados1050265
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